Human and animal studies suggest that decreased nitric oxide (NO) vasodilation and increased endothelin vasoconstriction are key components of the pathogenesis of pulmonary hypertension (PH). However, there are important areas of uncertainty and controversy regarding the roles of these two mediators, and better understanding of the regulation and interaction of NO and ET-1 in experimental models of PH would be useful in the development of more effective therapies for the diverse vascular disease. We have preliminary results that in contrast to the hypertensive lungs of chronically-hypoxic albino rats which express increased levels of eNOS MRNA and protein but little or no increase in ET-1, the spontaneously-hypertensive lungs of normoxic fawn-hooded rats express decreased levels of eNOS but high levels of ET-1 mRNA and peptide. These and other findings indicate that there are significant differences in the regulation of eNOS and ET-1 gene expression and NO1 and ET-1 vasoreactivity in these two animal models of PH. Thus, our overall hypothesis is that there are important differences in mechanisms of regulation of NO vasodilation and ET-1 vasoconstriction in different forms of PH. To test this idea, physiologic, pharmacologic, and molecular biologic techniques will be used in intact rats and isolated rat lungs to compare lung and pulmonary vascular gene expression, production, and vasoreactivity of NO and ET-1 in hypoxic versus spontaneous (fawn-hooded) PH. The specific aims are to test the hypothesis that: 1) while hypoxic PH is associated with increased expression of eNOS mRNA and protein but little increase in ET-1, spontaneous PH is accompanied by decreased expression of eNOS but high levels of ET-1, 2) hypertensive vascular tone is due to decreased No synthesis in hypoxic lungs and to high levels of ET-1 in fawn-hooded lungs and is differentially mediated by ETA and ETB receptors in the two models, 3) upregulation of eNOS in hypoxic hypertensive lungs is due to non-hemodynamic effects of hypoxia, and the increased expansion of ET-1 in spontaneously-hypertensive lungs is in response to hemodynamic signals.